Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA

Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2011; 108(7):3047-52. DOI: 10.1073/pnas.1010529108
Source: PubMed


Microbial colonization of mammals is an evolution-driven process that modulate host physiology, many of which are associated with immunity and nutrient intake. Here, we report that colonization by gut microbiota impacts mammalian brain development and subsequent adult behavior. Using measures of motor activity and anxiety-like behavior, we demonstrate that germ free (GF) mice display increased motor activity and reduced anxiety, compared with specific pathogen free (SPF) mice with a normal gut microbiota. This behavioral phenotype is associated with altered expression of genes known to be involved in second messenger pathways and synaptic long-term potentiation in brain regions implicated in motor control and anxiety-like behavior. GF mice exposed to gut microbiota early in life display similar characteristics as SPF mice, including reduced expression of PSD-95 and synaptophysin in the striatum. Hence, our results suggest that the microbial colonization process initiates signaling mechanisms that affect neuronal circuits involved in motor control and anxiety behavior.

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    • "Proof of principle studies in microbiota-deficient animals have clearly demonstrated a multifaceted impact of growing up germ-free during different neurodevelopmental stages at the level of the CNS. This extends from specific effects, for example, on the hippocampus in terms of neurogenesis (Ogbonnaya et al., 2015), neurotophic support (Desbonnet et al., 2015), synaptic integrity (Diaz Heijtz et al., 2011) and serotonin synthesis (Clarke et al., 2013) to the protection of the brain itself afforded by the blood brain barrier (Braniste et al., 2014). There is also a conceptual confluence between the behavioural effects demonstrated in these studies and more clinically relevant interventions such as early-life or adolescent antibiotic use (O'Mahony et al., 2014, Desbonnet et al., 2015). "
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    ABSTRACT: The prenatal and postnatal early-life periods are both dynamic and vulnerable windows for brain development. During these important neurodevelopmental phases, essential processes and structures are established. Exposure to adverse events that interfere with this critical sequence of events confers a high risk for the subsequent emergence of mental illness later in life. It is increasingly accepted that the gastrointestinal microbiota contributes substantially to shaping the development of the central nervous system. Conversely, several studies have shown that early-life events can also impact on this gut community. Due to the bidirectional communication between the gut and the brain, it is possible that aberrant situations affecting either organ in early life can impact on the other. Studies have now shown that deviations from the gold standard trajectory of gut microbiota establishment and development in early life can lead to not only disorders of the gastrointestinal tract but also complex metabolic and immune disorders. These are being extended to disorders of the central nervous system and understanding how the gut microbiome shapes brain and behavior during early life is an important new frontier in neuroscience.
    Neuroscience 10/2015; DOI:10.1016/j.neuroscience.2015.09.068 · 3.36 Impact Factor
    • "A functional link between the intestinal microbiota and neu- 58 ronal function in central nervous system has been convincingly 59 established in recent years, which appears to stem notably from 60 alterations in the host immune response (Rhee et al., 2009; 61 Cryan and Dinan, 2012; Burnet and Cowen, 2013; Forsythe and 62 Kunze, 2013). Germ-free mice display a reduction in the ability 63 to clear pathogens (Fritz et al., 2011), an exaggerated hypothala 64 mic–pituitary–adrenal (HPA) reaction to stress (Sudo et al., 2004) 65 and altered anxiety behaviour (Bercik et al., 2010; Neufeld et al., 66 2011; Diaz-Heijtz et al., 2011). Furthermore, the brains of germ- 67 free animals contain microglia that appear less mature than those 68 of specific pathogen free (SPF) mice and the transcriptome of these 69 microglia also suggests that they are less mature (Erny et al., 2015). "
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    ABSTRACT: The manipulation of the enteric microbiota with specific prebiotics and probiotics, has been shown to reduce the host’s inflammatory response, alter brain chemistry, and modulate anxiety behavior in both rodents and humans. However, the neuro-immune and behavioural effects of prebiotics on sickness behavior have not been explored. Here, adult male CD1 mice were fed with a specific mix of non-digestible galacto-oligosaccharides (Bimuno®, BGOS) for 3 weeks, before receiving a single injection of lipopolysaccharide (LPS), which induces sickness behaviour and anxiety. Locomotor and marble burying activities were assessed 4 hrs after LPS injection, and after 24 hrs, anxiety in the light-dark box was assessed. Cytokines expression, and key components of the serotonergic (5-Hydroxytryptamine, 5-HT) and glutamatergic system were evaluated in the frontal cortex to determine the impact of BGOS administration at a molecular level. BGOS-fed mice were less anxious in the light-dark box compared to controls, 24 hrs after the LPS injection. Elevated cortical IL-1 concentrations in control mice 28 hrs after LPS, was not observed in BGOS-fed animals. This significant BGOS x LPS interaction was also observed for 5HT2A receptors, but not for 5HT1A receptors, 5HT, 5HIAA, NMDA receptor subunits, or other cytokines. The intake of BGOS did not influence LPS-mediated reductions in marble burying behavior, and its effect on locomotor activity was equivocal. Together, our data show that the prebiotic BGOS hads an anxiolytic effect, which may be related to the modulation of cortical IL-1 and 5-HT2A receptor expression. Our data suggest a potential role for prebiotics in the treatment of neuropsychiatric disorders where anxiety and neuroinflammation are prominent clinical features.
    Brain Behavior and Immunity 10/2015; DOI:10.1016/j.bbi.2015.10.007 · 5.89 Impact Factor
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    • "In recent years, crosskingdom investigations have garnered attention, especially on the symbiotic bacteria in animals. The intestinal microbiota can play crucial roles in digestion, nutrition, and immune response of the animal hosts including human (Harris 1993; Turnbaugh et al. 2006; Renz et al. 2011) or during development , such as of the mammalian brain (Diaz Heijtz et al. 2011) and vertebrate gastrointestinal tract (Bouskra et al. 2008). In a recent study, Moran and Yun (2015) found that the pea aphid Acyrthosiphon pisum with the bacterium Buchnera increased in heat tolerance, demonstrating that the symbiont genotype can also affect the host ecology and, thus, its evolutionary history. "
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    ABSTRACT: During evolution of animals, their co-evolution with bacteria has generally been ignored. Recent studies have provided evidences that the symbiotic bacteria in the animal gut can either be essential or contributing to the plasticity of the host. The Crustacea includes crab, crayfish, lobster, and shrimp and represents the second largest subphylum on the planet. Although there are already studies investigating the intestinal bacterial communities in crustaceans, none of them has examined the microbiota in different parts of the digestive system during the gonad development of the host. Here, we utilized a new shrimp model Neocaridina denticulata and sequenced the 16S rRNA using the Ion Torrent platform to survey the bacterial populations colonizing the hepatopancreas, foregut, and intestine, including midgut and hindgut, of the early, mid, and late ovarian maturation stages of the shrimp. The predominant bacteria phylum was found to be Proteobacteria, with more than 80 % reads from the gut flora at the early gonad development belonged to a Coxiella-type bacterium. Distinct bacterial communities can be detected between the hepatopancreas and gut, although no significant difference could be revealed between the different regions of the gut investigated. Surprisingly, during the gonad development, bacterial diversity changed rapidly in the gut but not the hepatopancreas. This study provides the first evidence that microbiota modified differentially in specific regions of the digestive tract during gonadal development of crustaceans.
    Marine Biotechnology 08/2015; DOI:10.1007/s10126-015-9662-8 · 3.27 Impact Factor
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